US7964749B2 - Process for obtaining valine derivatives useful for obtaining a pharmaceutically active compound - Google Patents

Process for obtaining valine derivatives useful for obtaining a pharmaceutically active compound Download PDF

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US7964749B2
US7964749B2 US12/090,729 US9072906A US7964749B2 US 7964749 B2 US7964749 B2 US 7964749B2 US 9072906 A US9072906 A US 9072906A US 7964749 B2 US7964749 B2 US 7964749B2
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process according
compound
formula
valine
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US20100240919A1 (en
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Pere Dalmases Barjoan
Joan Huguet Clotet
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Inke SA
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Inke SA
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Assigned to INKE, S.A. reassignment INKE, S.A. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: DALMASES BARJOAN, PERE
Assigned to INKE, S.A. reassignment INKE, S.A. CORRECTIVE ASSIGNMENT TO ADD THE MISSING INVENTOR'S NAME, PREVIOUSLY RECORDED AT REEL 020957 FRAME 0778. ASSIGNOR(S) HEREBY CONFIRMS THE INKE, S.A. POL. IND. CAN PELEGRI - C ARGENT, 1 CASTELLBISBAL, SPAIN 08755. Assignors: BARJOAN, PERE DALMASES, CLOTET, JUAN HUGUET
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/10—Preparation of carboxylic acid amides from compounds not provided for in groups C07C231/02 - C07C231/08
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/53—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/54—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of a saturated carbon skeleton

Definitions

  • the present invention relates to a method for obtaining intermediates useful for obtaining a pharmaceutically active compound for manufacturing a drug for the treatment of arterial hypertension or heart failure.
  • the present invention relates to a method for obtaining intermediates useful in the synthesis of Valsartan.
  • Said Spanish patent describes the preparation of Valsartan by converting a phenyl substituent (Z 1 ) into tetrazole, where Z 1 is a group convertible into tetrazole.
  • Z 1 is a group convertible into tetrazole.
  • the examples of said patent describe the specific case in which Z 1 is a cyano group or a protected tetrazole ring. This is followed by final deprotection of the carboxylic acid group, where R is preferably methyl or benzyl and, if this is the case, of the tetrazole ring protecting group, preferably a trityl group.
  • Another negative aspect lies in the use of bulky protective groups both for the tetrazole ring (trityl group) and the carboxylic acid of the valine moiety (benzyl group), which very considerably increase the molecular weight of the last synthesis intermediate. This molecular weight is drastically reduced in the final hydrolysis to give Valsartan, thus resulting in a process of low atomic efficiency. This further creates a considerable amount of residues and increases the number of synthesis steps in the process.
  • Patents DE4313747, DE4407488, U.S. Pat. No. 5,596,006, EP594022 and WO9609301 describe the synthesis of sartans by formation of the biphenyl system by reacting an aryl halide with 2-(1H-tetrazol-5-yl)phenylboronic acid in the presence of a palladium catalyst.
  • European patent application EP1533305 describes a method for obtaining Valsartan by means of reductive amination reaction of a biphenyl aldehyde with protected L-valine with a benzyl group which has to be eliminated.
  • the tetrazole group is formed in the penultimate step of the synthesis.
  • Valsartan that is safe, ecological and with high yields and few synthesis steps and from simple and commercially available starting products. Additionally, it must be possible to apply the process on an industrial scale and to avoid racemisation and the consequent separation of enantiomers.
  • Patent application ES200400949 describes a process for the synthesis of Valsartan that includes reaction of the intermediate (II) with a boronic acid of formula (III) in order to give Valsartan (I):
  • Preparation of the Intermediate (II), in accordance with patent application ES200400949, comprises: a) alkylation of the L-Valine (IV) with a halide of formula (V) to give a compound of formula (VI) followed by b) acylation with valeryl chloride.
  • the carboxylic acid In the alkylation step the carboxylic acid must be protected in the form of silyl ester to prevent the formation of the benzyl ester. Furthermore, the dialkylation compound in the nitrogen of the L-Valine is inevitably formed in variable proportions and is difficult to eliminate.
  • reaction conditions are critical, and a restricted range of reaction parameters has to be used in order to prevent partial racemisation of compound (II) that would involve additional purifications.
  • a first aspect of the present invention is to provide an industrially viable process for obtaining the synthesis intermediate (II), useful in the preparation of Valsartan, and permitting it to be obtained with high yields and without racemisation.
  • a second aspect of the invention is to provide a method for obtaining the synthesis intermediate (II) with few synthesis steps.
  • work up is taken to mean the work of isolation and/or purification that is carried out once the reaction has finished. This involves, for example, extractions or precipitations in an aqueous medium.
  • one pot is taken to mean a series of consecutive reactions that are carried out without isolating the respective intermediates.
  • the object of the present invention is to provide a new process for obtaining the intermediate of formula (II), that permits it to be obtained with good yields, without racemisation, free from impurities and without problematic safety and environmental aspects.
  • X means halogen or an —OSO 2 R group, where R is CF 3 , tolyl, methyl or F;
  • X has the meaning defined above and B + is the protonated form of an organic base or an alkaline cation.
  • the process according to the invention does not use protective groups of the carboxylic acid group of the valine moiety in preparation of the synthesis intermediate (VI).
  • This is advantageous for what is understood as the atomic efficiency of the process, i.e. the proportion of atoms of the respective starting reagents that are incorporated into the desired product is optimum, and this translates into a considerable reduction of the amount of residues to be treated.
  • step a) the intermediate of formula (VIII) is obtained:
  • X means halogen or an —OSO 2 R group, where R is CF 3 , tolyl, methyl or F, and B + is the protonated form of an organic base or an alkaline cation, by means of an imination reaction of a benzaldehyde substituted in the position for (VII) by salts of the L-Valine with organic or inorganic bases.
  • the L-Valine is mixed with the 4-substituted benzaldehyde (VII) in the presence of an organic or inorganic base in equimolar proportion in relation to the L-Valine and a polar solvent or water at a temperature between 0° C. and the boiling temperature of the solvent, preferably between 10° C. and 35° C.
  • a substituted amine-type organic base may be used, such as triethylamine, trialkylamine, diisopropylethylamine (DIPEA) or a metallic alcoxide or hydroxide to form a salt of the L-Valine with an alkaline metal.
  • DIPEA diisopropylethylamine
  • the salt of an alkaline metal of the L-Valine can be prepared in situ in the reaction medium by the addition of bases such as hydroxides and alcoxylates, for example sodium hydroxide, potassium hydroxide, sodium methylate or sodium ethylate in a solution in methanol and optionally water.
  • bases such as hydroxides and alcoxylates, for example sodium hydroxide, potassium hydroxide, sodium methylate or sodium ethylate in a solution in methanol and optionally water.
  • the sodium salt can also be prepared independently by addition of a metal in elemental state, such as metallic sodium, to a solution of L-Valine in a polar solvent in the absence of water, such as anhydrous methanol.
  • the solvent of the reaction can be selected between water or a protic polar solvent.
  • the protic polar solvent is an alcohol, such as methanol, ethanol, 2-propanol, but more preferably methanol.
  • step b) the intermediate (VIII) is submitted to reductive conditions to obtain the compound (VI).
  • the reaction takes place in an alcoholic medium using borohydride as reducing agent, such as sodium borohydride, lithium borohydride, calcium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride.
  • borohydride as reducing agent, such as sodium borohydride, lithium borohydride, calcium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride.
  • the reduction can also be carried out by means of catalytic hydrogenation in the presence of hydrogen and of a metallic catalyst at atmospheric pressure, or by transfer of hydrogen in the presence of a metallic catalyst and a hydrogen donor such as formic acid, 2-propanol, ethanol, etc.
  • the metallic catalyst used can be Raney-Nickel or a palladium, rhodium or ruthenium catalyst, preferably a palladium catalyst.
  • the reduction is carried out with sodium borohydride.
  • racemisation of the chiral centre present in the molecule is prevented. This is an additional advantage over methods that involve the utilisation of carboxylic group protective groups, since the deprotection conditions can lead to racemisation.
  • This process has the advantage that it does not require protection of the carboxyl group of the L-Valine.
  • the reductive amination reaction has the additional advantage of preventing formation of the dialkylation product.
  • step c) the compound (VI) obtained is made to react with valeryl chloride in order to provide the intermediate (II):
  • X means halogen or an —OSO 2 R group, where R is CF 3 , tolyl, methyl or F.
  • This step c) of the process is characterised in that it consists in N-acylation of the compound of formula (VI) with valeryl chloride, without the protection of carboxylic acid:
  • said aprotic organic solvent is selected from tetrahydrofuran (THF), dimethoxyethane (DME) and acetonitrile. More preferably still, it is tetrahydrofuran (THF).
  • an organic base will be selected from a heterocyclic compound that contains one or more atoms of nitrogen.
  • said heterocyclic compound with at least one atom of nitrogen is chosen from pyridine or pyridines substituted with one or more methyl groups, such as collidines or lutidines; or imidazole or imidazole substituted with a methyl group such as 2-methylimidazole or 4-methylimidazole. More preferably still, 2-methylimidazole is used.
  • step c) takes place in the presence of 1 or 2 equivalents of water in relation to the amount of starting product (VI).
  • the presence of water in said reaction prevents racemisation of the asymmetric carbon.
  • said N-acylation is carried out at a temperature between ⁇ 10 and 10° C.
  • a method for obtaining the synthesis intermediate (II) with few synthesis steps, where the compound of formula (VI) can be obtained by means of a one-pot reaction from the starting products (VII) and (IV), without need to isolate the imine compound (VIII).
  • the compound of formula (II) is achieved with good yields and in two reaction steps, since the one-pot reaction is carried out according to the conditions set out in steps a) and b) to obtain the compound of formula (VI) from simple and commercially available raw materials.
  • the product obtained according to the first or second aspects of the invention can be purified by conventional methods such as recrystallisation in a single solvent or in a mixture of a solvent and antisolvent, for example ethanol/water, ethyl acetate/hexane, dichloromethane/heptane, isopropyl acetate/methylcyclohexane.
  • a solvent and antisolvent for example ethanol/water, ethyl acetate/hexane, dichloromethane/heptane, isopropyl acetate/methylcyclohexane.
  • the invention provides a method for obtaining the intermediate of formula (II) without racemisation from a compound of formula (VI) that does not require the protection of the carboxylic acid.
  • the compound of formula (VI) is obtained with an optical purity of 99.5-100%.
  • Valsartan is obtained with good chemical yield and high optical purity by means of a process applicable on an industrial scale and starting from simple and commercially available products through synthesis intermediates that do not require protection of the tetrazolic ring or of the carboxylic acid of the L-Valine moiety, nor the use of sodium azide or tributyl tin azide, thereby improving the safety of the process and reducing its environmental impact.
  • a mixture formed by 11.4 g (40 mmol) of N-(4-bromobenzyl)-L-Valine and 60 mL of THF is cooled to ⁇ 5° C., and 2.8 mL (50 mmol) of HAcO, 7.6 mL (64 mmol) of valeryl chloride and a solution of 4.9 g (60 mmol) of 2-methylimidazole in 30 mL of THF and 1.4 mL (80 mmol) of H 2 O are added to it.
  • the reaction mixture is stirred for 30 minutes at room temperature, 10 mL of methanol is added to it, it is then stirred for a further 15 minutes and 40 mL of H 2 O is added to it.
  • the phases are separated and the organic phase is evaporated to dryness and the solid obtained is recrystallised from a mixture of EtOH:H 2 O 1:1.
  • Example 5 In a manner similar to Example 5 and starting from 12 g (32 mmol) of N-(4-tosylbenzyl)-L-Valine, 6.2 mL (51 mmol) of valeryl chloride and 3.95 g (48 mmol) of 2-methylimidazole, 11 g (75%) of N-(4-toluen-4-sulphonyl)-benzyl)-N-valeryl-L-Valine is obtained. The solid is recrystallised from a mixture of n-Heptane:EtAcO 10:1.
  • IR (KBr, cm-1): 2957, 1714, 1575, 1469, 1362, 1249, 1173, 1092, 862, 748, 688, 660.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
US12/090,729 2005-10-20 2006-10-19 Process for obtaining valine derivatives useful for obtaining a pharmaceutically active compound Expired - Fee Related US7964749B2 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
ES200502558 2005-10-20
ESP-200502558 2005-10-20
ES200502558A ES2288376B1 (es) 2005-10-20 2005-10-20 Procedimiento para la obtencion de intermedios utiles en la obtencion de un compuesto farmaceuticamente activo.
PCT/EP2006/067569 WO2007045675A1 (fr) 2005-10-20 2006-10-19 Procede d’obtention de derives de valine utiles pour la fabrication d’un compose pharmaceutiquement actif

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US20100240919A1 US20100240919A1 (en) 2010-09-23
US7964749B2 true US7964749B2 (en) 2011-06-21

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US (1) US7964749B2 (fr)
EP (1) EP1937654B1 (fr)
JP (1) JP2009512661A (fr)
CN (1) CN101309910A (fr)
AT (1) ATE448212T1 (fr)
DE (1) DE602006010423D1 (fr)
ES (1) ES2288376B1 (fr)
WO (1) WO2007045675A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009125416A2 (fr) 2008-04-07 2009-10-15 Hetero Research Foundation Procédé de préparation d'un intermédiaire de valsartan
CN107987125A (zh) * 2017-11-23 2018-05-04 爱斯特（成都）生物制药股份有限公司 一种缬氨酸衍生物的制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004026847A1 (fr) * 2002-09-23 2004-04-01 Novartis Ag Procede de fabrication de valsartan
US7439261B2 (en) * 2003-11-21 2008-10-21 Dipharma S.P.A. Process for the preparation of valsartan and intermediates thereof
US20090124577A1 (en) * 2004-12-22 2009-05-14 Enantia Si Intermediate Compounds for the Preparation of an Angiotensin II Receptor Antagonist
US7728021B2 (en) * 2004-04-20 2010-06-01 Inke, S.A. Process for the preparation of Valsartan and precursors thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004026847A1 (fr) * 2002-09-23 2004-04-01 Novartis Ag Procede de fabrication de valsartan
US7439261B2 (en) * 2003-11-21 2008-10-21 Dipharma S.P.A. Process for the preparation of valsartan and intermediates thereof
US7728021B2 (en) * 2004-04-20 2010-06-01 Inke, S.A. Process for the preparation of Valsartan and precursors thereof
US20090124577A1 (en) * 2004-12-22 2009-05-14 Enantia Si Intermediate Compounds for the Preparation of an Angiotensin II Receptor Antagonist

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EP1937654A1 (fr) 2008-07-02
WO2007045675A1 (fr) 2007-04-26
EP1937654B1 (fr) 2009-11-11
ATE448212T1 (de) 2009-11-15
ES2288376B1 (es) 2008-11-01
JP2009512661A (ja) 2009-03-26
DE602006010423D1 (de) 2009-12-24
ES2288376A1 (es) 2008-01-01
CN101309910A (zh) 2008-11-19
US20100240919A1 (en) 2010-09-23

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